chr12-51242388-A-C

Variant names:

• chr12-51242388-A-C
• rs746134764
• NM_014764.4:c.437A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014764.4(DAZAP2):​c.437A>C​(p.Asn146Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,696 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N146S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: DAZAP2 NM_014764.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.54
• Publications: 0 publications found

Genes affected

DAZAP2 (HGNC:2684): (DAZ associated protein 2) This gene encodes a proline-rich protein which interacts with the deleted in azoospermia (DAZ) and the deleted in azoospermia-like gene through the DAZ-like repeats. This protein also interacts with the transforming growth factor-beta signaling molecule SARA (Smad anchor for receptor activation), eukaryotic initiation factor 4G, and an E3 ubiquitinase that regulates its stability in splicing factor containing nuclear speckles. The encoded protein may function in various biological and pathological processes including spermatogenesis, cell signaling and transcription regulation, formation of stress granules during translation arrest, RNA splicing, and pathogenesis of multiple myeloma. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.827

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014764.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAZAP2	NM_014764.4	MANE Select	c.437A>C	p.Asn146Thr	missense	Exon 4 of 4	NP_055579.1	Q15038-1
	DAZAP2	NM_001136266.2		c.360A>C	p.Gln120His	missense	Exon 4 of 4	NP_001129738.1	Q15038-5
	DAZAP2	NM_001136264.2		c.371A>C	p.Asn124Thr	missense	Exon 5 of 5	NP_001129736.1	Q15038-6

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DAZAP2	ENST00000412716.8	TSL:1 MANE Select	c.437A>C	p.Asn146Thr	missense	Exon 4 of 4	ENSP00000394699.2	Q15038-1
	DAZAP2	ENST00000549555.5	TSL:2	c.360A>C	p.Gln120His	missense	Exon 4 of 4	ENSP00000448051.1	Q15038-5
	DAZAP2	ENST00000905427.1		c.401A>C	p.Asn134Thr	missense	Exon 4 of 4	ENSP00000575486.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461696 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.00 AC: 0 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1111894

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.50
BayesDel_addAF	Benign	-0.037	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.054	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Benign	-0.74	T
PhyloP100		6.5
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.32
Sift	Benign	0.054	T
Sift4G	Benign	0.56	T
Polyphen		0.89	P
Vest4		0.78
MutPred		0.66		Gain of glycosylation at N146 (P = 0.0129)
MVP		0.55
ClinPred		0.98	D
GERP RS		5.4
Varity_R		0.28
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs746134764; hg19: chr12-51636172;